Clinical experience with anti-inflammatory agents in patients with sepsis has been disappointing to date. We have found that several factors such as the site, type, and severity of infection have important influences on many of these agents. Developing new agents which are impacted minimally by such factors, will increase the usefulness of this therapeutic approach. The role of endotoxin in the injury of sepsis is unclear. It is likely that under many circumstances it produces harmful effects. Targeting endotoxin rather than host mediators may be a more generally useful goal in sepsis. Antibodies against endotoxin have had little effect to date in sepsis because the toxic lipid portion of the molecule may be difficult to target. An alternative approach to neutralizing endotoxin uses analogue molecules which competitively inhibit cell signaling by endotoxin. We are currently performing a series of studies investigating the influence of site, severity, and type of infection on a competitive inhibitor of endotoxin.